Hot flushes during the perimenopausal and post-menopausal periods pose a significant public health concern because they (i) are the primary reason that women seek medical care during the menopausal transition; (ii) often negatively impact the quality of life for women because they are associated with depression, sleep disturbances resulting in fatigue, irritability, and forgetfulness, as well as acute physical discomfort and negative effects on work; and (iii) are thought to be indicative of some impending, serious conditions. Despite the importance of hot flushes in a woman's life, little is known about the underlying mechanism or the risk factors for hot flushes. Although the most efficacious therapy for hot flushes is estrogen replacement therapy, due to the potential risks involved with hormone therapy, many women try to find alternative therapies, such as the selective serotonin and/or serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs), clonidine, and gabapentine in spite of their lower efficacy compared to estrogen replacement therapy. Clinical and preclinical data indeed show that these neurotransmitters play critical roles in thermoregulation by changing the sensitivity of the thermostat and subsequently, affecting hot flushes. Although a subpopulation of perimenopausal women do respond to SSRIs/NRIs, the response is heterogenous (some individuals respond well some do not respond at all). The overall goal of this application is to explore why some women with hot flushes do not respond to SSRIs/SNRIs. Our hypothesis is that the heterogenouos response is due to single nucleotide polymorphisms of the serotonin transporter (SERT) and/or the norepinephrine transporter (NET) genes. Therefore, we propose the following specific aims: (1) Genotype a comprehensive set of SNPs within the SERT and NET genes in a sample of 800 perimenopausal women recruited during a previous funding period and 58% of whom experienced hot flushes and genotype these genes in a sample of 200 women being recruited and (2) Determine whether these SNPs are correlated with hot flushes. This proposal matches the R21 funding requirements in that it explores, for the first time, the relationship between SNPs of SERT and NET genes as predictors of hot flush relief. If the heterogeneous response to SSRI/SNRI therapies is due to these SNPs, then a customized, genotype-based therapy may be the ultimate solution to increase efficacy of this approach to treating bothersome hot flushes without hormones. PUBLIC HEALTH RELEVANCE: Although hot flushes during the perimenopausal period pose a significant public health concern. Little is known about the underlying mechanism of hot flushes. Many women try to find alternative therapies, to estrogen such as the selective serotonin and/or serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs). However, the response to these is heterogenous and might be due to individual gene variations. This proposal will identify these variations and their relationship to hot flushes.